Patent GB-1398291-A (GB)
Title: Prostaglandin analogues and production thereof
IPC: C07C405/00
Filed: 1972-04-27
Abstract: 1398291 Prostaglandins; acylmethane phosphonates ONO PHARMACEUTICAL CO Ltd 27 April 1972 [30 April 1971 17 Nov 1971] 10 Dec 1971] 19706/72 Headings C2C and C2P [Also in Division C3] The invention comprises optically active prostaglandins of the formulae IX, X, XI, XII XIII and XIV wherein X 1  is 3-(R or S)-hydroxy-4-(R or S) methyl - trans - 1 - octenyl, 3 - (S) - hydroxy- 4,4 - dimethyl - trans - 1 - octenyl, or 4 - ethyl- 3-(S)-hydroxy-trans-1-octenyl, the esters thereof, salts thereof, the cyclodextrin clathrates thereof and the esters thereof, PG alcohol derivatives thereof, and the dihydro-PG 1  derivatives thereof, and optically active prostaglandins of the Formulae XV and XVII wherein THP is 2-tetrahydropyranyl and X 2  is 4-(R or S)-methyl-3-(R or S)-tetrahydropyran- 2<SP>1</SP> - yloxy - trans - 1 - octenyl, 4,4 - dimethyl - 3- (S) - tetrahydropyran - 2<SP>1</SP> - yloxy - trans - 1- octenyl, or 4-ethyl-3-(S)-tetrahydropyran-21- yloxy-trans-1-octenyl and their preparation The PGA analogues of Formulae XIII and XIV are prepared by dehydrating the corresponding PGE analogues of the Formulae XI and XII, which are made by oxidizing the 9- hydroxy group in compounds of the Formulae XV and XVII and hydrolysing the resulting products. PGF analogues of the Formulae IX and X are prepared by hydrolysing the corresponding PGF analogues of the Formulae XV and XVII. The dihydro-PG 1  analogues are obtained by hydrogenating the corresponding PG 1  analogues. The corresponding ester, alcohols, salts and cyclodextrin clathrates are prepared by standard methods. PGF 1  analogues of the Formula XVII are made by the selective hydrogenation of the corresponding PGF 2  analogues of the Formula XV which are prepared by reacting 4-carboxybutylidenetriphenylphosphorane with cyclopenta[b]p-urans of the formula obtained by reducing the corresponding lactones, resulting from the etherification of the corresponding 5a-hydroxy-4#-X 1 -3,3a#,4,5,6,6a#-hexahydro-2H-cyclopenta[b]-furan-2-ones, which are made by hydrolysing the appropriate 5α- acetoxy - 4# - X 1  - 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclopenta[b]furan - 2 - ones, obtained by reducing the corresponding 5α- acetoxy - 4# - (3 - oxo - octenyl) - 3,3a#,4,5,6,6a#- hexahydro - 2H - cyclopenta[b]furan - 2 - ones, which are prepared by reacting 5α-acetoxy-4#- formyl - 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclopenta[b]furan-2-one with the appropriate dimethyl or diethyl 2-oxoheptylphosphonates. 4α - Hydroxy - 2α - (7 - hydroxy - cis - 2- heptenyl) - 3# - (3 - (S) - hydroxy - 4 - (S)- methyl - trans - 1 - octenyl)cyclopentanone oxime is obtained by reducing 4α-hydroxy-2α-(6- methoxycarbonyl - cis - 2 - hexenyl) - 3# - (3 - (S)- hydroxy - 4 - (S) - methyl - trans-1-octenyl)cyclopentanone oxime, which is prepared by reacting the methyl ester of 16-(S)-methyl-PGE 2  with hydroxylamine hydrochloride. Dimethyl - 2 - oxo - 3 - methylheptylphosphonate, dimethyl - 2 - oxo - 3,3 - dimethylheptylphosphonate and dimethyl-2-oxo-3-ethylheptylphosphonate are prepared by dimethyl methylphosphonate with ethyl 2-methylhexanoate, ethyl 3,3-dimethylhexanoate and ethyl 2-ethylhexanoate respectively in the presence of butyllithium. Pharmaceutical compositions, suitable for oral, parenteral, sublingual, vaginal and rectal administration, contain the prostaglandins of the Formulae IX to XIV or derivatives thereof and suitable carriers. The compounds possess similar activities to those of naturally occurring prostaglandins. Reference has been directed by the Comptroller to Specification 1,198,071.